Structure-based optimization of protein tyrosine phosphatase 1B inhibitors: from the active site to the second phosphotyrosine binding site

J Med Chem. 2007 Sep 20;50(19):4681-98. doi: 10.1021/jm0702478. Epub 2007 Aug 17.


Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of the insulin and leptin receptor pathways and thus an attractive therapeutic target for diabetes and obesity. Starting with a high micromolar lead compound, structure-based optimization of novel PTP1B inhibitors by extension of the molecule from the enzyme active site into the second phosphotyrosine binding site is described. Medicinal chemistry, guided by X-ray complex structure and molecular modeling, has yielded low nanomolar PTP1B inhibitors in an efficient manner. Compounds from this chemical series were found to be actively transported into hepatocytes. This active uptake into target tissues could be one of the possible avenues to overcome the poor membrane permeability of PTP1B inhibitors.

MeSH terms

  • Animals
  • Binding Sites
  • Caco-2 Cells
  • Catalytic Domain
  • Cell Membrane Permeability
  • Crystallography, X-Ray
  • Half-Life
  • Hepatocytes
  • Humans
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microsomes, Liver / metabolism
  • Models, Molecular*
  • Molecular Structure
  • Phosphotyrosine / chemistry
  • Phosphotyrosine / metabolism*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Tyrosine Phosphatases / antagonists & inhibitors*
  • Protein Tyrosine Phosphatases / chemistry
  • Rats
  • Rats, Sprague-Dawley
  • Solubility
  • Structure-Activity Relationship
  • Thiophenes / chemical synthesis*
  • Thiophenes / pharmacokinetics
  • Thiophenes / pharmacology
  • Tissue Distribution


  • Thiophenes
  • Phosphotyrosine
  • PTPN1 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Tyrosine Phosphatases
  • Ptpn1 protein, mouse
  • Ptpn1 protein, rat